BACE camp: anti-amyloid Alzheimer's therapies at AAIC

Merck & Co, Eli Lilly and Eisai are all presenting clinical data on a new class of anti-dementia agent - BACE inhibitors - at this week's Alzheimer's Association International Conference (AAIC).

BACE or beta-secretase is an enzyme involved in the conversion of amyloid precursor protein (APP) into amyloid beta, which is deposited as plaques in the brains of patients with Alzheimer's disease.

Inhibitors of BACE are designed to interrupt this process, prevent the formation of plaques and - assuming the amyloid hypothesis of Alzheimer's is correct - interrupt the cascade of events that lead to degeneration of neurons in the disease.

Merck & Co will present additional early clinical data on its MK-8931 candidate at the AAIC meeting, including a study which reveals that it lowers amyloid beta levels in the cerebrospinal fluid (CSF) of healthy volunteers. Earlier this year, Merck reported phase I trial data indicating MK-8931 was well-tolerated and achieved marked reductions in plasma amyloid beta concentration levels.

Meanwhile, Eisai is scheduled to present the first clinical data on E2609, indicating that the BACE inhibitor can reduce plasma amyloid beta levels after a single dose, as well as significant reductions in CSF levels after 14 days of oral dosing.

Finally, Lilly is presenting preclinical and early-stage clinical research on its LY2886721 candidate, which is currently in a phase I/II study in Alzheimer's patients with mild cognitive impairment.

The crop of BACE inhibitors is following behind a number of other amyloid-targeting therapies - notably Eli Lilly's solanezumab and Pfizer/Elan's bapineuzumab - that are expected to provide the first clear indication of whether the approach is valid in patients with Alzheimer's.

Both solanezumab and bapineuzumab are due to report pivotal trial data later this year and work by targeting already-formed amyloid beta in central nervous system. Even if they prove ineffective, there may be value in blocking amyloid beta production upstream, and BACE inhibition is one way to achieve that.

Another approach is to target the gamma secretases, which also convert APP into amyloid beta, although this class has suffered a number of disappointments, notably Lilly's semagacestat which was discontinued in 2010 after late-stage studies revealed serious side effects.

More selective gamma secretase inhibitors such as Bristol-Myers Squibb's avagecestat (BMS-708163) remain in development, and the company presented clinical data from a phase II trial at AAIC yesterday. It has said it wants to gauge the drug's effect on biomarkers in ongoing trials before it decides whether to press ahead with a phase III programme.

Some scientists argue that BACE - and particularly one form of the enzyme known as BACE1 - may be a superior target to gamma secretase because it is found predominantly in the brain and not in other parts of the body. Merck, Eisai and Lilly's drug candidates are all selective BACE1 inhibitors.